Peripheral inflammation, due to arthritis or trauma, often results in facilitated nociceptive processing in the spinal cord. Spinal cord changes are in part responsible for the clinical states of allodynia (decreased threshold to pain) and hyperalgesia (increased sensitivity to pain). Recent data suggest that plastic changes may be initiated by spinal release of excitatory amino acids (EAAs) and substance P (SP) and maintained by the spinal actions of prostanoids and/or nitric oxide (NO). To explore these hypotheses further, extracellular spinal cord concentrations of prostaglandin E2 (PGE2) and amino acids, including citrulline, a co-product of NO synthesis, will be measured in lightly anesthetized rats. Basal concentrations and release evoked by electrical sciatic nerve stimulation at low (AalphaBeta fiber) and high (A+C) intensities, or by intradermal injection of capsaicin, will be measured in normal rats and in rats in which the acute stimulus is superimposed upon a state of facilitated neurotransmission. Models of central facilitation used will be advanced kaolin/carrageenan experimental arthritis and phase 2 of the formalin test. Preliminary studies indicate that several neurohormonal agents are released during these states and that release of EAAs and PGE2 evoked by C fiber stimulation increases after induction of arthritis. Parallel studies involving intrathecal (IT) administration of EAAs, SP, PGE2 and an NO donator molecule will serve as comparisons to the inflammation models. Behavioral studies indicate that these agents induce hyperalgesia when given spinally. IT administration of agonists will provide a standard against which spinal actions of receptor-specific antagonists to EAAs and SP as well as synthesis inhibitors for PGE2 and NO can be screened. Effective antagonists will be used as pre- (prior to induction of a facilitated state by arthritis or formalin injection) and post- (after a facilitated state has been produced) treatments to ascertain if their actions antagonize augmented release. Special attention will be paid to the NO and prostanoid systems. Behavioral studies have shown that spinal administration of many of these agents blocks peripheral injury induced hyperalgesia. PGE2 will be measured via RIA and amino acids with HPLC. Results of these experiments will answer 1) which neurohormonal agents are released during development of central facilitation, 2) whether exogenous spinal administration of these agents leads to the release of endogenous agonists and 3) whether blockade of either the prostanoid or NO system, as either pre-or post-treatment, antagonizes sensitization- associated changes. The long-term goals of this work are 1) to determine the pharmacological sequence of events leading to increased output of dorsal horn neurons to a fixed input and the concomitant sensory disturbances that occur during arthritis and other forms of peripheral inflammation and 2) to determine the most efficacious way in which to antagonize or re verse the sensitization. Such information would present significant possibilities for the development of novel analgesics, and provide insights into the mechanisms of some already in use.